Thrombophila and venous thromboembolism

Jan Kvasnička, Prague,CZ

• Venous thrombosis is a multifactorial disease and analysis of the interactions between acquired and inherited risk factors is an extremely interesting field of investigation

Introduction

A Silent Killer:VTE

VTE: Magnitude of the Problem in the United States

1Hirsh J & Hoak J. Circulation 1996;93:2212-452Pengo V et al. N Engl J Med 2004;350:2257-64

3Brandjes DP et al. Lancet 1997;349:759-624Kahn SR et al. J Gen Intern Med 2000;26:425-9

60,0001

600,0001

800,0003,4

30,0002

2 million1

VTE: Magnitude of the Problem in the United States

Asymptomatic DVT

Death

PE

Post-thrombotic syndrome

Symptomatic DVT

Pulmonary hypertension

VTE According to Service (N=384)

0 25 50 75 100 125 150 175Other

Thoracic surgery

Orthopaedic surgery

Medical oncology

General surgery

Medical

Number of VTE events

Total VTEPEDVT

44

16

10

9

8

14

Goldhaber SZ et al. Chest 2000;118:1680-4

Total VTE (%) Patients

VTE: United States

• VTE accounts for >250,000 hospitalizations in the USA annually1,2

– PE has a 3-month mortality rate as high as 17%3

– VTE may lead to the debilitating post-phlebitic syndrome in as many as 33% of patients4

1Anderson F Jr et al. Arch Intern Med 1991;151:933-82Kim V et al. Emerg Med Clin North Am 2001;19:839-59

3Goldhaber SZ et al. Lancet 1999;353:1386-94Prandoni P et al. Ann Intern Med 1996;125:1-7

VTE: Europe

• France: about 100,000 new cases of DVT are diagnosed each year and 20,000 fatal cases of PE per year2

• Germany: 180,000 new cases of DVT each year and 30,000–40,000 fatal cases of PE per year

• Chronic thromboembolic pulmonary hypertension after PE: cumulative incidence 3.8% at 2 years (95% CI 1.1 to 6.5%)3

• UK: 90,000 cases of VTE each year of which 54,000 cases are PE1

1Datamonitor 20032Blanchemaison P. Phlébologie 1998;51:87-90

3Pengo V et al. N Engl J Med 2004;350:2257-64

Partsch H et al. Phlebologie 2000;29:106CI = confidence interval

Incidence of PE:Hospital vs General Population

0

0,1

0,2

0,3

0,4

0,5

0–9 10–19 20–29 30–39 40–49 50–59 60–69 70–79 80–89Age (years)

Annu

al in

ciden

ce o

f PE

in

a te

rtiar

y-ca

re g

ener

al

hosp

ital1

(% h

ospi

tal a

dmiss

ions

) PE is up to 10-fold higher in hospital

population than in general population1–3

1Stein PD et al. Chest 1999;116:909-132Anderson F Jr et al. Arch Intern Med 1991;151:933-8

3Silverstein MD et al. Arch Intern Med 1998;158:585-93

acquired risk factors for VTE• age, • surgery,• neoplasm,• reduced mobility or paresis,• among women - estrogen hormonal status (oral contraceptive, hormone replacement therapy,

pregnancy ) is responsible for the majority of all venous thrombotic events,

• previous episode of deep vein thrombosis,• controversial impact of other factors : obesity, tobacco use

and varicose veins.

Oger E. et al. Ann Cardiol Angiol (Paris). 2002 Jun;51(3):124-8.

Annual incidence of venous thromboembolism among Olmsted County,

Minnesota residents, 1966-90, by age and gender

Disease Associations

• Evidence-based– cardiac disease (acute MI/acute heart failure – NYHA III/IV)– infectious disease/sepsis– active cancer requiring therapy– respiratory diseases (respiratory failure with/without mechanical

ventilation; exacerbation of chronic respiratory disease)– rheumatic disease (including acute arthritis of lower extremities,

vertebral compression, and acute back disorders)– neurological disorders (stroke, paraplegia)

• Consensus-based– inflammatory disorders with immobility– inflammatory bowel disease

Primary diagnosis requiring admission or bedrest in patients >40 years

Cohen AT et al. J Thromb Haemost 2003;1 Suppl 1:OC437MI = myocardial infarctionNYHA = New York Heart Association

Exposing Risk Factors inMedical Patients

Chronic obstructive pulmonary disease 2.90

Myocardial infarction 3.33

Acute cardiac heart failure,Stages NYHA III/IV 3.00

Pulmonary oedema 3.41

Ischaemic stroke without paralysis 2.89

Ischaemic stroke with paralysis 5.00

Malignant disease requiring treatment 4.22

Septicaemia, severe infections 3.89

Samama MM et al. Haematologica 2003; 88:1410-21

Odds Ratio

NYHA = New York Heart Association

Risk Factors for VTE (1)

• Strong risk factors (odds ratio >10)– fracture (hip or leg)– hip or knee replacement– major general surgery– major trauma– spinal cord injury

Anderson F & Spencer F. Circulation 2003;107:I09-I16

Risk Factors for VTE (2)• Moderate risk factors (odds ratio 2–9)

– arthroscopic knee surgery– central venous line– chemotherapy– CHF/respiratory failure– HRT/oral contraceptive therapy– malignancy– previous VTE– paralytic stroke– pregnancy/post-partum– thrombophilia

CHF = congestive heart failureHRT = hormone replacement therapy Anderson F & Spencer F. Circulation 2003;107:I09-I16

Risk Factors for VTE (3)

• Weak risk factors (odds ratio <2)– bedrest >3 days– sitting for prolonged periods, e.g. >8 hours of

air travel– increased age– laparoscopic surgery– obesity– pregnancy/antepartum– varicose veins

Anderson F & Spencer F. Circulation 2003;107:I09-I16

Score of exposing risk

Individual Risk Assessmentfor Orthopaedic Surgery/Trauma

THR/TKR surgery Multiple trauma Spinal surgery in presence of neurological disorders Arthroscopy Plaster cast of lower limb Spinal surgery in absence of neurological disorders Operation <30 min Upper-limb surgery Pin or plate removal

High(3)

Moderate(2)

Low(1)

Score of predisposing risk

1

0

2

3

0.5 1.5 2.5

High risk

Moderate risk

Age 60–70 years Malignancy 1.0

Obesity Major varicosis 0.5 Oestrogens (>50 g)

Thrombophilic state History of VTE 1.5 Age >70 years

THR = total hip replacementTKR = total knee replacement

Haas S. In: Meßmer K, Witte J, editors. Was gibt es Neues in der Chirurgie? Eco-med Verlag; Jahresband, 2002

1

0

2

3

Lowrisk

Increasedrisk

Lutz L, Haas S, Hach-Wunderle V, et al. Venous thromboembolism in internal medicine: risk evaluation and drug prophylaxis. Med Welt

2002;53:231-4

0 1 2 3

Class of predisposing risk Dehydration Polycythaemia or thrombocytosis Varicosis VTE in family HRT Obesity

Thrombophilia History of VTE Active malignancy or 3 risks from category 1 2 risks from category 2

No basic risk Age 65 years Pregnancy Oral contraception Nephrotic syndrome Myeloproliferative syndrome 2 risks from category 1

0 1 2 3

Ischaemic stroke with paralysis Acute decompensation of COPD with ventilation MI Heart failure NYHA III + IV Acute decompensation of COPD without ventilation Sepsis Infection/acute inflammatory disease: bedrest Infection/acute inflammatory disease: non-strict bedrest Central venous lines or port system No acute risk 0

1

2

3

COPD = chronic obstructive pulmonary diseaseHRT = hormone replacement therapy

Individual Risk Assessmentfor Internal Medicine Patients

Class of exposing risk

THROMBOPHILIA • (synonymum hypercoagulable state) - has been referred to as hereditary and / or acquired tendency to thrombosis. • therefore the people with hereditary thrombophilia are at constant, lifelong risk of thrombosis.

thrombusthrombophilia

stimulus

Thrombogenesis A.I.Schafer (Lancet,1994,344:1739)

VT is multifactorial disease, presence of different factors raises the risk : e.g. - relative risk of VT while thrombophilia FVL is approx. 2 -3x , but relative risk of VT while FVL and O.C. is 30x higher than in persons without these .

Genetic studies• More than 40 genetic polymorphisms were

described in over 25 hemostasis - related genes,

but only 2 of these polymorphisms have been consistently associated with thrombosis:

• mutation FV-Leiden 1691 GA,• mutation FII 20210 GA.

Prevalence of Biologic Defects in Patients with Venous Thrombosis

• Activated Protein C Resistance (Factor V Leiden) 12 - 40%• Prothrombin G20210A Mutation 6 - 18%• Deficiencies of Antithrombin III, PC, PS 5 - 15%• Hyperhomocysteinemia 10 - 20%• Antiphospholid Antibody Syndrome 5 - 10%

• Screening for resistance to activated protein C (APC) with clotting assay that dilutes patient plasma in factor – V defficient plasma (confirm positive APC resistance assay genetically) or genetic test for Factor V – Arg506Gln (Factor – V Leiden)

• Genetic test for prothrombin G20210A mutation• Functional assay of antithrombin III (heparin-cofactor assay)• Function assay of protein C • Function assay of protein S along with immunological assays of total

and free protein S• Clotting assay for lupus anticoagulant/ELISA for cardiolipin

antibodies (IgG and IgM)• Meassurment of fasting total plasma homocysteine levels

Laboratory Evaluation of Hypercoagulability

FV Leiden (Arg506Gln)

Real time – PCR Light cycler (Roche)

Crucial role in molecular medicine and clinical diagnostics, quick and reliable diagnostics.

Performs rapid PCR in less than 30 min, simultaneously quantify and analyze the results by monitoring fluorescence during amplification.

Detect mutations: changes in the melting curve analysis can be used to identify mutations.

Methods

• We included 496 carriers of FVL (208 male and 287 female) who were

treated at our Thrombotic Centre and ICEM Prague for VT, and age of the first VT episode was recorded.

• The FVL was tested by a conventional DNA amplification and restriction enzyme analysis / or by a real time PCR using Light cycler ® in the cohort of pts.

Ocurrence of first VT in male carriers of Factor V Leiden mutation

Ocurrence of first VT in female carriers of Factor V Leiden mutation.

Results

The majority of the first VTs in FVL carriers registered for VTE in our centres were :• at 20 - 29 years in female FVL carriers

(26,5% from all; 68% used O.C.) and • at 40 - 49 years in male FVL carriers (24,4 % from all; 47% surgery or trauma

related) .

Num

ber o

f pat

ient

swi

th fa

tal P

E P<0.005

Prophylaxis of Fatal, Postoperative PE with Low-dose UFH

16

2

02468

1012141618

Control UFH

Lancet 1975;2:45-51Low-dose UFH saves 7 lives for every 1,000 operated patients

LMWH

Medianmolecular

weight Xa/IIaratio

Enoxaparin 4,500 3.3Dalteparin 5,000 2.0Nadroparin 4,500 3.0Tinzaparin 6,500 1.8Reviparin 3,900

Anti-Xa IU/mg

104 122 94 90 130

Anti-IIa IU/mg

32 60 31 50 40 3.3

Drug prescribing information

Clear Benefits of Thromboprophylaxis over

Placebo

MEDENOX1 63% PlaceboEnoxaparin 40 mg

PREVENT2 49% PlaceboDalteparin

ARTEMIS3 47% PlaceboFondaparinux

14.9*

5.5

Study RRR Thromboprophylaxis Patients with VTE (%)

5.0*2.8

10.5†

5.6

*VTE at day 14; †VTE at day 15.1Samama MM et al. N Engl J Med 1999;341:793-800 2Leizorovicz A et al. Circulation 2004;110:874-9

3Cohen AT et al. J Thromb Haemost 2003;1 (Suppl 1):P2046

P<0.001

P=0.0015

P=0.029

RRR = relative risk reduction

RRR

63%

45%

47%

Global Findings Presented at the International Society on Thrombosis& HaemostasisGeneva – July 8, 2007

A global observational study of venous thromboembolism risk and prophylaxis in the acute care hospital setting

Study design

Multinational, cross-sectional survey of

the prevalence of VTE risk andprophylaxis use

in hospital patients

Objectives• Primary

– To identify patients at risk for venous thromboembolism (VTE) hospitalized in representative hospitals throughout the world

– To determine the proportion of patients who receive effective VTE prophylaxis

• Secondary

– To define the above globally by acute illness (in medical and surgical populations)

A worldwide study

32 countries -- 358 hospitals32 countries -- 358 hospitalsFirst patient enrolled August 2, 2006Last patient enrolled January 4, 2007

Median of 8 days to enroll eligible patients/hospital

Criteria for VTE risk and recommendations for prophylaxis

2004 American College of Chest Physicians Recommendations*• Medical and surgical patients at risk• Appropriate types of prophylaxis

*Geerts WH, et al. Chest. 2004;126(Suppl 3):338S-400S

High Bleeding Risk

• Intracranial hemorrhage• Hepatic impairment• Bleeding at hospital admission• Active gastro-duodenal ulcer• Known bleeding disorders

ACCP-2004 risk criteria and recommendations in medical patients

Acutely ill medical patients admitted to the hospital• heart failure • severe respiratory disease

Who are confined to bed with ≥ 1 additional factors

• active cancer • previous VTE• acute neurological disease • sepsis• inflammatory bowel disease

ICU patients who are moderate risk for VTE

Geerts WH, et al. Chest. 2004;126(Suppl 3):338S-400S

Medical risk patients: LMWH, UFH

Patients in medical wards who met ACCP risk criteria (N = 15,487 / 37,356)

Medical patientsat ACCP-definedVTE risk

42%

Patients in surgical wards who met ACCP risk criteria (N =19,842 / 30,827)

Surgical patientsat ACCP-definedVTE risk 64%

Patients at risk for VTE and receiving ACCP recommended prophylaxis

Primary objectives

52% at risk for VTE

50% received ACCPrecommended Px

Overall( N= 68,163 )

42% at risk for VTE

48% received ACCPrecommended Px

Medical( n = 37,356 )

Secondary objectives

64% at risk for VTE

59% received ACCPrecommended Px

Surgical( n = 30,827 )

Conclusions• First global view of VTE risk and prophylaxis practices

• Unprecedented scope– 32 Countries, 358 Hospitals, 68,183 Patients

• Risk for VTE is common (52%)– 64% of surgical patients– 42% of medical patients

• Prophylaxis is underutilized (50%)– Surgical patients: Omitted in 41%– Medically ill population: Omitted in 60%

• ENDORSE findings demonstrate the high prevalence of patients at risk for VTE and the need to improve the rate of prophylaxis use

These data reinforce the rationale to

• Urgently implement hospital-wide strategies

• Systematically assess patient risk for VTE

• Provide appropriate prophylaxis to prevent VTE

Biotechnology-derived

heparin-like drugsOral and

parenteralantithrombin

drugs

Heparinoids

Anti-TFdrugs

Activated protein C

Generic versions

of branded LMWHs

Coagulation

protease inhibitors

Recombinantserpins

Oralheparin and

GAGsNewer developments in

antithrombotic therapy

Anti-Xa drugs

GAGs = glucosaminoglycans; TF = tissue factor

Conclusion I• It is known that the majority of VTE may

be considered to be preventable, but the patients at increased risk must be firstly identified.

• In contrary to this fact, the laboratory testing of inherited thrombophilia was not recommended for its screening on the costbenefit basis till now.

Conclusion II

• We suggest , the next investigation of thrombophilic states for prevention of VTE at increased risk conditions (e.g.before starting of O.C.) will be very efficient after adopting new research tools in our practice , such as non-expensive SNP testing in the near future.